Intra-arterial Drug Administration Research Articles

Neuroradiological diagnosis and therapy of cerebral vasospasm after subarachnoid hemorrhage.

Cerebral damage after aneurysmal subarachnoid hemorrhage (SAH) results from various, sometimes unrelated causes. After the initial hemorrhage trauma with an increase in intracranial pressure, induced vasoconstriction, but also microcirculatory disturbances, inflammation and pathological electrophysiological processes (cortical spreading depolarization) can occur in the course of the disease, resulting in delayed cerebral ischemia (DCI). In the neuroradiological context, cerebral vasospasm (CVS) remains the focus of diagnostic imaging and endovascular therapy as a frequent component of the genesis of DCI. The amount of blood leaked during aneurysm rupture (which can be detected by CT, for example) correlates with the occurrence and severity of CVS. CT perfusion is then an important component in determining the indication for endovascular spasm therapies (EST). These include intra-arterial drug administration (also as long-term microcatheter treatment) and mechanical procedures (balloon angioplasty, vasodilatation using other instruments such as stent retrievers, stenting). This review summarizes the current findings on the diagnosis and treatment of CVS after aneurysmal SAH from a neuroradiological perspective, taking into account the complex and up-to-date international literature. · Vasospasm is a frequent component of the multifactorial genesis of delayed cerebral ischemia after SAH and remains the focus of diagnosis and treatment in the neuroradiological context.. · The initial extent of SAH on CT is associated with the occurrence and severity of vasospasm.. · CT perfusion is an important component in determining the indication for endovascular spasm therapy.. · Endovascular spasm therapies include local administration of medication (also as long-term therapies with microcatheters) and mechanical procedures (balloon angioplasty, dilatation using other devices such as stent retreivers, stenting).. · Neumann A, Schacht H, Schramm P. Neuroradiological diagnosis and therapy of cerebral vasospasm after subarachnoid hemorrhage. Fortschr Röntgenstr 2024; 196: 1125 - 1133.

Breaking Barriers in Neuro-Oncology: A Scoping Literature Review on Invasive and Non-Invasive Techniques for Blood-Brain Barrier Disruption.

The blood-brain barrier (BBB) poses a significant challenge to drug delivery for brain tumors, with most chemotherapeutics having limited permeability into non-malignant brain tissue and only restricted access to primary and metastatic brain cancers. Consequently, due to the drug's inability to effectively penetrate the BBB, outcomes following brain chemotherapy continue to be suboptimal. Several methods to open the BBB and obtain higher drug concentrations in tumors have been proposed, with the selection of the optimal method depending on the size of the targeted tumor volume, the chosen therapeutic agent, and individual patient characteristics. Herein, we aim to comprehensively describe osmotic disruption with intra-arterial drug administration, intrathecal/intraventricular administration, laser interstitial thermal therapy, convection-enhanced delivery, and ultrasound methods, including high-intensity focused and low-intensity ultrasound as well as tumor-treating fields. We explain the scientific concept behind each method, preclinical/clinical research, advantages and disadvantages, indications, and potential avenues for improvement. Given that each method has its limitations, it is unlikely that the future of BBB disruption will rely on a single method but rather on a synergistic effect of a combined approach. Disruption of the BBB with osmotic infusion or high-intensity focused ultrasound, followed by the intra-arterial delivery of drugs, is a promising approach. Real-time monitoring of drug delivery will be necessary for optimal results.

Chinese expert consensus on intra-arterial drug and combined drug administration for primary hepatocellular carcinoma

Transarterial interventional therapy is one of the most widely used treatment methods in patients with primary hepatocellular carcinoma. With the progress in interventional technology and the use of new drugs, transarterial interventional therapy has achieved favorable results in the treatment of primary hepatocellular carcinoma and has become the first choice non-surgical treatment for advanced liver cancer. However, at present, there are great differences in the drugs used in transarterial interventional treatment and the combined application of other drugs among centers, and there is no uniform consensus or guideline. Based on the latest research data and clinical practice experience, as well as the characteristics of Chinese patients, the Specialist Group of Interventional Drugs, Interventionalists Branch of the Chinese Medical Doctor Association was organized to formulate the Chinese expert consensus on intra-arterial drug and combined drug administration for primary hepatocellular carcinoma. The purpose of this consensus is to explore the efficacy and safety of drugs and drug combinations related to intra-arterial interventional therapy, the use of drugs in special populations, the management of adverse reactions, and adjuvant drugs to provide a reference for clinical practice.

Method of intra-arterial drug administration in a rat: Sex based optimization of infusion rate

BackgroundEndovascular thrombectomy is the process of removing a blood clot and re-establishing blood flow in patients with emergent large vessel occlusion. The technique provides an opportunity to deliver therapeutics directly to the site of injury. The intra-arterial (IA) route of drug administration in the mouse was developed to bridge the gap between animal stroke treatments and clinical stroke therapy. Here, we adapted the IA method for use in rats, by investigating various flow rates to optimize the IA injection through the internal carotid artery (ICA). MethodsMale and female Sprague-Dawley rats (∼4 months of age) were subjected to placement of micro-angio tubing at the bifurcation of the common carotid artery for injection into the ICA. We evaluated a range of infusion rates of carbon black ink and its vascular distribution within the brain. ResultsOptimal injection rates in males was 4−6 μl/min and 2−4 μl/min in females. The IA injection using these sex-specific rates resulted in appropriate limited dye delivery to only the ipsilateral region of the brain, without inducing a subarachnoid hemorrhage. ConclusionUpon adapting the IA administration model to rats, it was determined that the rate of infusion varied between males and females. This variability is an important consideration for studies utilizing both sexes, such as in ischemic stroke studies.

Ultrasound-Guided Stellate Ganglion Block to Treat Accidental Injection of Propofol in an Anomalous Radial Artery

Intra-arterial drug administration is a rare but potentially dreadful condition which can result in ischemia and gangrene of the hand. In the present case we accidentally injected propofol in an anomalous radial artery during anesthesia induction. Serial ultrasound-guided stellate ganglion blocks were applied to salvage the limb of the patient by promoting arterial blood flow. This is probably the first reported case of accidental intra-arterial injection of propofol being managed with stellate ganglion block.

Regional Chemotherapy Infusion Via the Bronchial Artery in Combined Treatment of Non-Small Cell Lung Cancer

Introduction. Chemotherapy in the form of endovascular infusion or its combination with radiotherapy is a method for treating non-small cell lung cancer (NSCLC), which raises heated discussions among specialists. This study is aimed at assessing the early results of combined treatment of NSCLC patients with selective chemotherapy infusion via the bronchial artery.Materials and methods. A retrospective analysis of treatment results for 24 patients with central pulmonary cancer hospitalized in the Shymkent Oncological Centre (Kazakhstan) during 2016–2019 was carried out. The average age of the patients was 46.4 ± 11.3 years. According to the histological study, 19 and 5 patients were diagnosed with squamous cell lung cancer and undifferentiated carcinoma, respectively. The patients were recognized as surgically incurable; three courses of neoadjuvant polychemotherapy via selective catheterization of the bronchial artery and regional intra-arterial administration of drugs were prescribed according to the DR scheme: Docetaxel 75 mg/m2 , Cisplatin 75 mg/m2 .Results and discussion. Upon completion of three courses of selective chemotherapy, 20 (83.3%) patients showed the possibility of surgical treatment: 15 patients underwent extended pulmonectomy, 5 patients underwent extendedcombined pulmonectomy with pericardial resection with intrapericardial, separate processing of the vessels of the lung root. After the surgical stage, all patients received radiation therapy to the mediastinal area at a single tumour dose of 2 Gy and a total radiation dose of 45–50 Gy. According to an analysis of the mortality and survival rates, 28-day mortality comprised 5% (1 patient, whose death occurred as a result of acute cardiovascular failure); one-year survival rate was 91.6%.Conclusions. Preliminary results of our study show that selective chemotherapy via the bronchial artery increases the frequency of surgical interventions and the overall survival of patients with inoperable pulmonary cancer.

Interleukin 1 alpha administration is neuroprotective and neuro-restorative following experimental ischemic stroke

BackgroundStroke remains a leading cause of death and disability worldwide despite recent treatment breakthroughs. A primary event in stroke pathogenesis is the development of a potent and deleterious local and peripheral inflammatory response regulated by the pro-inflammatory cytokine interleukin-1 (IL-1). While the role of IL-1β (main released isoform) has been well studied in stroke, the role of the IL-1α isoform remains largely unknown. With increasing utilization of intravenous tissue plasminogen activator (t-PA) or thrombectomy to pharmacologically or mechanically remove ischemic stroke causing blood clots, respectively, there is interest in pairing successful cerebrovascular recanalization with neurotherapeutic pharmacological interventions (Fraser et al., J Cereb Blood Flow Metab 37:3531–3543, 2017; Hill et al., Lancet Neurol 11:942–950, 2012; Amaro et al., Stroke 47:2874–2876, 2016).MethodsTransient stroke was induced in mice via one of two methods. One group of mice were subjected to tandem ipsilateral common carotid artery and middle cerebral artery occlusion, while another group underwent the filament-based middle cerebral artery occlusion. We have recently developed an animal model of intra-arterial (IA) drug administration after recanalization (Maniskas et al., J Neurosci Met 240:22–27, 2015). Sub groups of the mice were treated with either saline or Il-1α, wherein the drug was administered either acutely (immediately after surgery) or subacutely (on the third day after stroke). This was followed by behavioral and histological analyses.ResultsWe now show in the above-mentioned mouse stroke models (transient tandem ipsilateral common carotid artery (CCA) and middle cerebral artery occlusion (MCA) occlusion, MCA suture occlusion) that IL-1α is neuroprotective when acutely given either intravenously (IV) or IA at low sub-pathologic doses. Furthermore, while IV administration induces transient hemodynamic side effects without affecting systemic markers of inflammation, IA delivery further improves overall outcomes while eliminating these side effects. Additionally, we show that delayed/subacute IV IL-1α administration ameliorates functional deficit and promotes neurorepair.ConclusionsTaken together, our present study suggests for the first time that IL-1α could, unexpectedly, be an effective ischemic stroke therapy with a broad therapeutic window.

Vandetanib-eluting Radiopaque Beads: Pharmacokinetics, Safety, and Efficacy in a Rabbit Model of Liver Cancer.

Background Transarterial chemoembolization with cytotoxic drugs is standard treatment for unresectable intermediate-stage hepatocellular carcinoma but achieves suboptimal outcomes because of hypoxic stress and the production of detrimental proangiogenic factors. An alternative approach using radiopaque embolization beads loaded with the antiangiogenic drug vandetanib may provide improved anticancer efficacy. Purpose To evaluate the pharmacokinetics, safety, and efficacy of vandetanib-eluting radiopaque bead (VERB) chemoembolization of rabbit liver tumors. Materials and Methods Between April 2015 and March 2016, 60 New Zealand white rabbits with VX2 liver tumors were randomly treated with VERBs at different doses, with nonloaded radiopaque beads (ROBs), or with intra-arterial vandetanib suspension (VS) or were not treated. Vandetanib plasma concentration and tumor growth at US were evaluated. Animals were euthanized after 3 days or 3 weeks. Assessment included bead distribution at x-ray imaging and histologic examination, tumor viability at histologic examination, and vandetanib tissue concentration. Group comparison analysis (Mann-Whitney, Kruskal-Wallis, and χ2 tests) and predictive factor analysis for tumor growth and viability were performed. Results Vandetanib plasma concentration was lower with VERBs than with VS (P < .01), while concentration in tumor was higher for VERBs (than for VS) at 3 days (median, 29.2 vs 2.74 ng/mg; P = .48). Tumor growth was lower with VERBs than with ROBs and with VS at both time points, with median values of +114%, +192%, and +466% at 3 weeks, respectively. Tumor viability was lower at 3 days for VERBs than for ROBs and for VS (3%, 18%, and 38%, respectively) but was not significantly different at 3 weeks. The volume of bead in tumor was a significant predictive factor for lower tumor growth in multivariable analysis at 3 days (P = .03). Drug tumor concentration was a significant predictive factor for lower tumor growth at 3 weeks (P = .04). Conclusion Vandetanib-eluting radiopaque bead chemoembolization showed a pharmacokinetic advantage over intra-arterial drug administration in a preclinical model of liver cancer. High deposition of beads and high vandetanib concentration in tumor led to stronger antitumor effects. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Kim and Van den Abbeele in this issue.

Intra-arterial infusion chemotherapy versus isolated upper abdominal perfusion for advanced pancreatic cancer: a retrospective cohort study on 454 patients

PurposeThe treatment of pancreatic carcinoma remains a challenge as prognosis is poor, even if confined to a single anatomical region. A regional treatment of pancreatic cancer with high drug concentrations at the tumor site may increase response behaviour. Intra-arterial administration of drugs generates homogenous drug distribution throughout the entire tumor volume.MethodsWe report on treatment outcome of 454 patients with advanced pancreatic carcinoma (WHO stage III: 174 patients, WHO stage IV: 280 patients). Patients have been separated to two different treatment protocols. The first group (n = 233 patients) has been treated via angiographically placed celiac axis catheters. The second group (n = 221 patients) had upper abdominal perfusion (UAP) with stopflow balloon catheters in aorta and vena cava. Both groups have been treated with a combination of cisplatin, adriamycin and mitomycin.ResultsFor stage III pancreatic cancer, median survival rates of 8 and 12 months were reached with IA and UAP treatment, respectively. For stage IV pancreatic cancer, median survival rates of 7 and 8.5 months were reached with IA and UAP treatment, respectively. Resolution of ascites has been reached in all cases by UAP treatment. Toxicity was generally mild, WHO grade I or II, toxicity grade III or IV was only noted in patients with severe systemic pretreatment. The techniques, survival data and detailed results are demonstrated.ConclusionsResponsiveness of pancreatic cancer to regional chemotherapy is drug exposure dependent. The isolated perfusion procedure is superior to intra-arterial infusion in survival times.

A murine model of targeted infusion for intracranial tumors.

Historically, intra-arterial (IA) drug administration for malignant brain tumors including glioblastoma multiforme (GBM) was performed as an attempt to improve drug delivery. With the advent of percutaneous neuorovascular techniques and modern microcatheters, intracranial drug delivery is readily feasible; however, the question remains whether IA administration is safe and more effective compared to other delivery modalities such as intravenous (IV) or oral administrations. Preclinical large animal models allow for comparisons between treatment routes and to test novel agents, but can be expensive and difficult to generate large numbers and rapid results. Accordingly, we developed a murine model of IA drug delivery for GBM that is reproducible with clear readouts of tumor response and neurotoxicities. Herein, we describe a novel mouse model of IA drug delivery accessing the internal carotid artery to treat ipsilateral implanted GBM tumors that is consistent and reproducible with minimal experience. The intent of establishing this unique platform is to efficiently interrogate targeted anti-tumor agents that may be designed to take advantage of a directed, regional therapy approach for brain tumors.

Techniques for endovascular treatment of acute ischemic stroke: from intra-arterial fibrinolytics to stent-retrievers.

Early recanalization of occluded vessels in acute ischemic stroke (AIS) either by intravenous thrombolysis or endovascular revascularization has been shown to be associated with improved clinical outcome and reduced mortality.1 Initial works on endovascular treatment (EVT) of AIS was published in the 1980s.2,3 Since then, the endovascular techniques for AIS treatment have tremendously improved, advancing from intra-arterial administration of thrombolytic drugs to first-generation mechanical thrombectomy devices (Merci clot retriever and Penumbra clot aspiration) and more recently to second-generation mechanical thrombectomy devices (stent-retrievers; Figure 1). Introduction of various tools and techniques in EVT for AIS will, for obvious reasons, affect the efficacy and safety. Figure 1. Evolution of endovascular techniques for acute ischemic stroke and clinical trials. IMS indicates Interventional Management of Stroke; MERCI, Mechanical Embolus Removal in Cerebral Ischemia; MR CLEAN, Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands; PROACT, Prolyse in Acute Cerebral Thromboembolism; SWIFT, Solitaire With the Intention for Thrombectomy; and TREVO, Thrombectomy Revascularization of Large Vessel Occlusions in Acute Ischemic Stroke. On the other hand, intravenous thrombolysis was evaluated in several large randomized trials and was shown to improve clinical outcome at 90 days if treatment was initiated within 3 hours of stroke onset.4 Subsequently, the European Cooperative Acute Stroke Study (ECASS) III showed the benefit of intravenous thrombolysis between 3 and 4.5 hours.5 After establishing the efficacy of intravenous recombinant tissue-type plasminogen activator (r-tPA) in the treatment of AIS, EVT had to be evaluated against intravenous treatment. A long time elapsed before the results of the first randomized controlled trials were published in 2013 demonstrating no major difference between intravenous r-tPA treatment and EVT for AIS.6–8 Noteworthy, these trials had several limitations including the fact that all EVT were approved for use.9 …

Selective intra-arterial drug administration in a model of large vessel ischemia.

With continuing disconnect between laboratory stroke treatment models and clinical stroke therapy, we propose a novel experimental model to study stroke and vessel recanalization that mirrors acute management of large vessel stroke, with concomitant directed pharmacotherapy. Using the tandem transient ipsilateral common carotid/middle cerebral artery occlusion (MCAO) model to induce stroke in mice we then added selective intra-arterial (IA) drug administration for directed pharmacotherapy. The IA model uses micro-angio tubing placed at the bifurcation of the CCA to selectively administer the drug to the internal carotid distribution. We have shown that delivery of pharmacotherapy agents selectively through an IA injection is feasible in a mouse model, which will permit studies involving pharmacotherapy, transgenic modification, and/or a combination. Our IA model has similarities to previously published models of IA injection but differs in that we do not leave an indwelling micro-port or catheter in our animals, which is not clinically relevant as it does not reflect the human condition or current clinical management. Furthermore, we optimized our model to selectively direct therapy to the ipsilateral, stroke affected hemisphere. By developing an IA drug delivery model that mirrors clinical conditions, we are bridging the gap between basic stroke research and what is standard practice in acute ischemic stroke intervention. The IA model of drug delivery can target agents directly to the site of injury while blunting systemic effects, dose penetration issues, and administration delay that have plagued the intraperitoneal and oral drug administration models.

Infraclavicular brachial plexus block for the management of inadvertent intraarterial drug administration after arterial insertion of a venous cannula during ultrasound-guided venous cannulation.

This case report documents the inadvertent placement of an arterial cannula despite using realtime ultrasound to insert a peripheral venous cannula in a child with difficult venous access. The resultant limb ischemia was treated with an infraclavicular ultrasound-guided brachial plexus block as sympatholytic treatment.

Association of Anxiety With Resistance Vessel Dysfunction in Human Atherosclerosis

Anxiety predicts cardiovascular events, although the mechanism remains unclear. We hypothesized that anxiety symptoms will correlate with impaired resistance and conduit vessel function in participants aged 55 to 90 years. Anxiety symptoms were measured with the Symptom Checklist-90--Revised in 89 participants with clinically diagnosed atherosclerotic cardiovascular disease and 54 healthy control participants. Vascular function in conduit arteries was measured using flow-mediated dilatation, and vascular function in forearm resistance vessels (FRVs) was measured using intra-arterial drug administration and plethysmography. Anxiety symptoms were not associated with flow-mediated dilatation in either group. Participants with atherosclerosis exhibited significant inverse associations of anxiety symptoms with FRV dilatation (acetylcholine: β = -.302, p = .004). Adjustment for medication, risk factors, and depression symptoms did not alter the association between anxiety and FRV dysfunction, except for body mass index (BMI; anxiety: β = -.175, p = .060; BMI: β = -.494, p < .001). Although BMI was more strongly associated with FRV function than anxiety, combined BMI and anxiety accounted for greater variance in FRV function than either separately. Control participants showed no association of anxiety with FRV function. Anxiety is uniquely and substantially related to poorer resistance vessel function (both endothelial and vascular smooth muscle functions) in individuals with atherosclerosis. These relationships are independent of medication, depression, and cardiovascular risk factors, with the exception of BMI. These findings support the concept that anxiety potentially increases vascular events through worsening of vascular function in atherosclerotic disease.

Abstract 4477: Safety and efficacy of intracarotid administration of temozolomide in a rat model of intracerebral metastasis.

Abstract Purpose: Temozolomide (Temodar; Merck) is an alkylating chemotherapeutic agent used to treat glioblastoma and other brain malignancies. After oral administration, the average brain interstitium to plasma area under the drug concentration-time curve ratio for temozolomide has been reported as approximately 0.2 in animal models and patients. We hypothesized that intra-arterial (IA) drug administration into the internal carotid artery would improve temozolomide delivery to brain tissue, with subsequent increased anti-tumor efficacy. Methods: Athymic nude rats received intracerebral implantation of LX-1 human small cell lung carcinoma cells as a model of chemosensitive brain metastasis, and were studied 10 days after cell implantation when tumors measured 10-30 mm3 in volume. To assess drug delivery, rats received 25 μCi 14C-temozolomide by oral, intravenous (IV), or IA/osmotic blood-brain barrier disruption (BBBD) route of administration (n = 5-7 per group). Radiolabeled drug in tumor and brain was measured 10 min after drug administration by quantitative autoradiography. To assess efficacy, rats received either no treatment or a single treatment with 20 mg/kg temozolomide (∼150 mg/m2) by oral, IV, or IA route of administration (n = 8 per group) and rats were followed for survival. Results: The ratio of drug delivery in tumor compared to normal left hemisphere was equivalent for the oral (2.51 ± 25) and IV (2.56 ± 0.87) routes (P = 0.90). After IA/BBBD, the tumor to brain ratio was 4.11 ± 1.12 and tumor-specific 14C-radioactivity was 85.4 ± 29.9 nCi/gram tissue, compared to 38.1 ± 19.9 nCi/gram tissue after IV administration (P = 0.019 by Student t-test). Median survival in untreated control rats was 17.5 days. A single temozolomide dose was effective at increasing survival when given by oral (median survival 25.5 days), IV (25.5 days), or IA (33 days) route of administration (overall P&amp;lt;0.0001 by the Log Rank test). Survival times in the oral and IV groups were significantly longer than control (P&amp;lt;0.001) but did not differ from each other, while survival time in the IA group was significantly longer than all other groups (P&amp;lt;0.01 for all comparisons). Temozolomide could not be given with BBBD in the efficacy study due to toxicities likely related to the diluent; there was no evidence of neurotoxicity in rats given IA temozolomide. Conclusions: Infusion of temozolomide into the internal carotid artery improved drug delivery and safely increased efficacy in a rat intracerebral tumor model. The improved efficacy suggests that a clinical trial of IA temozolomide is warranted in refractory glioblastoma. Citation Format: Leslie L. Muldoon, Michael A. Pagel, Edward A. Neuwelt. Safety and efficacy of intracarotid administration of temozolomide in a rat model of intracerebral metastasis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4477. doi:10.1158/1538-7445.AM2013-4477

Methotrexate and/or Rituximab in a New Nude Rat Central Nervous System Lymphoma Model: Efficacy, Toxicity and Magnetic Resonance Imaging.

The aim of this study was to determine the efficacy and toxicity of methotrexate (MTX) and/or rituximab treatment in a novel central nervous system (CNS) lymphoma model, using either intravenous (IV) or intraarterial (IA) drug administration in conjunction with osmotic blood-brain barrier disruption (BBBD). Female athymic nude rats (rnu/rnu) were inoculated with human MC116 B-cell lymphoma cells in the caudate putamen. On the day of treatment and first magnetic resonance imaging (MRI) (day 16–20), rats were randomized into 7 groups:1.control group with saline IV (n = 15) or2.IA/BBBD (n = 7);3.rituximab 375 mg/m2 IV (n = 6) or4.IA/BBBD (n = 3);5.MTX 1000 mg/m2 IV (n = 6) or6.IA/BBBD (n = 6); and7.rituximab 375 mg/m2 IV + MTX 1000 mg/m2 IV (n = 6).A second MRI scan was done 1 week after treatment. Study end points included tumor response on MRI (defined as ≤75% tumor volume on post-treatment MRI), toxicity, and tumor volumes on histology. In the IV groups, the percent change in tumor volume on T2/FLAIR images in the control versus rituximab group was statistically significant (p = 0.0051). In the IA/BBBD groups, there was a statistically significant difference between control and rituximab (p = 0.0167) for absolute and percent changes in tumor volumes on both T2/FLAIR and T1 with gadolinium sequences. For T1 with gadolinium, the difference between control and MTX was also significant for both absolute change (p = 0.0066) and percent change (p = 0.0043). Response rates in the IV groups differed significantly between controls and rituximab (p = 0.0017 on T2/FLAIR and p = 0.0049 on T1 with gadolinium). A good correlation between tumor volumes (in log mm3) on histology and fluid-attenuated inversion recovery (FLAIR)/T2 (R2 = 0.83) or contrast-enhanced T1 weighted images (R2 = 0.73) for tumors located in the caudate putamen was observed. Results of complete blood counts at sacrifice did not differ significantly between the groups. The MC116 CNS lymphoma model is valuable for preclinical testing of efficacy and toxicity of various treatment regimens. Rituximab and MTX were particularly effective in this model, regardless of the route of administration.

Endovaskuläre Behandlung des Schlaganfalls

Standard therapy of acute ischaemic stroke during the first three hours after symptom onset is intravenous thrombolysis. When contraindications exist, an endovascular approach might be possible. Intraarterial administration of thrombolytic drugs is the most common way. Additionally, there is an increasing use of mechanical tools that are expected to be faster and more effective. Three principles of mechanical thrombolysis are known: aspiration, extraction and fracturing of the thrombus. Different tools were tested clinically and some demonstrated its high efficiency. Larger studies are needed to compare those tools. Apart from recanalization of a cerebral vessel occlusion implantation of a stent might be necessary for prophylaxis of recurrent stroke.

Ceravolo

Gemcitabine is considered the gold standard treatment for unresectable pancre-atic adenocarcinoma. Intra-arterial drug administration had shown some interesting results in small phase II studies.In this study, patients were randomly assigned to receive gemcitabine at a dose of 1,000 mg/m2 over 30 minutes intravenously weekly for 7 weeks, followed by 1 week of rest, then weekly for 3 weeks every 4 weeks or FLEC: 5-fluoruracil 1,000 mg/m2, leucovorin 100 mg/m2, epirubicin 60 mg/m2, carboplatin 300 mg/m2 infused bolus intra-arterially into celiac axis at a 3-week interval 3 times or 5-fluor-ouracil 400 mg/m2 plus folinic acid 20 mg/m2 for 5 days every 4 weeks for 6 cycles. The primary endpoint was overall survival, while time to treatment failure, response rate, clinical benefit response were secondary endpoints. Sixty-seven patients were randomly allocated gemcitabine and 71 were allocated FLEC intra-arterially. Patients treated with FLEC lived for significantly longer than patients on gemcitabine (p=0.036). Survival at 1 year increased from 21% in the gemcitabine group to 35% in the FLEC group. Median survival was 7.9 months in the FLEC group and 5.8 months in the gemcitabine group. Median time to treatment failure was longer with FLEC (5.3 vs 4.2 months for FLEC vs gemcitabine respectively; p=0.013). Clinical benefit was similar in both groups (17.9% for gemcitabine and 26.7% for FLEC; p=NS). CT-scan partial response was similar in both groups (5.9% for gemcitabine and 14% for FLEC; p=NS). Toxicity profiles were different.Compared with gemcitabine, the FLEC regimen given intra-arterially improved survival in patients with unresectable pancreatic adenocarcinoma.

Differing effects of N(G)-monomethyl L-arginine and 7-nitroindazole on detrusor activity.

Previous studies reported that nitric oxide (NO) synthase (NOS) inhibition decreases micturition volume threshold (MVT), the volume required to produce a centrally mediated micturition contraction, and that NO can be released from urothelium by means of certain stimuli. With elucidation of multiple isoforms of NOS, studies were performed to determine whether inhibition of specific isoforms of NOS altered MVT in different ways. In naive, anesthetized cats, the urinary bladder was exposed by means of a midline abdominal incision and cannulated through a slit in the internal urethra approximately 4-5 cm distal to the neck of the bladder. The left renal artery and left radial vein were cannulated for the intra-arterial and intravenous administration of drugs, respectively. All nerves were left intact. A control MVT was determined by slowly infusing saline into the bladder at a rate of 0.018 mL/kg per minute. Varying doses of L-NMMA (N(G)-monomethyl-L-arginine) or 7-NI (7-nitro indazole) were administered and the MVT was again determined. Inhibition of endothelial NOS (eNOS), by L-NMMA, or neuronal NOS (nNOS), by 7-NI, produces varying effects on certain detrusor activities and that inhibition of different isoforms of NOS produces qualitatively different effects. L-NMMA significantly decreases MVT (up to 60% decrease), whereas 7-NI significantly increases MVT (over 300% increase). L-NMMA increases frequency and onset of small bladder contractions, whereas 7-NI produces opposite effects. The results suggest that detrusor relaxation and contractility may be modulated by NO levels and that NO released from the urothelium may be a mediator of detrusor relaxation during the storage phase of micturition.

Venous occlusion plethysmography in cardiovascular research: methodology and clinical applications.

The use of venous occlusion plethysmography to measure blood flow in humans was first described over 90 years ago by Hewlett & van Zwaluwenburg [1]. Although initially limited by the need for cumbersome equipment, the advent of mercury-in-silastic strain gauges over 50 years ago greatly increased its applicability, and the technique has remained essentially unchanged since except for the introduction of computerization. Venous occlusion plethysmography has been used extensively to study human vascular physiology in vivo, and is at its most powerful when combined with intra-arterial drug administration, usually into the forearm vascular bed. This permits detailed study of both vascular pharmacology, usually by infusion of receptor agonists, and physiology, by infusion of receptor antagonists. Indeed, forearm venous occlusion plethysmography with local brachial artery infusion has become one of the ‘gold-standards’ in the assessment of vascular function in health and disease, and an accurate, reproducible and convenient method with which to assess the effect of new vasoactive drugs and hormones in humans in vivo [2]. Besides being minimally invasive, the major advantage of this approach is that drugs can be administered at subsystemic doses minimizing disturbances to systemic physiology. Although venous occlusion plethysmography can be equally well applied to the lower limb, this review will focus on the forearm vascular bed.